Esophageal carcinoma is the eighth most common cancer and the sixth leading cause of cancer-related mortality worldwide. The incidence of esophageal cancer varies widely by histology and geographic region. Over the past four decades, the predominant histological type in the United States (US) has shifted drastically from esophageal squamous-cell carcinoma (ESCC) to esophageal adenocarcinoma (EA). In China and its surrounding areas, however, ESCC is the predominant type; EA remains rare without association of Barrett's esophagus (BE). While prevention and therapeutic strategies are urgently needed, the genetic and environmental architecture of EA etiology that underwrites this profound temporal, spatial and histological variation remains unclear. Recent high-throughput genomic studies have made progress in understanding germline and somatic mutations of EA. Signi?cant gaps remain for understanding genetic basis of EA. First, how do genetic susceptibility loci contribute to risk prediction for EA, in concert with the risk factors that hav been studied for over 20 years? Second, what are mutated genes that drive carcinogenesis of EA, given the majority of somatic mutations already occur in BE and most BE cases do not progress to EA? In this project, we propose genomic studies for understanding the etiology of esophageal adenocarcinoma, leveraging existing genome-wide association data and cancer genome data. A number of innovative approaches will be undertaken include integrative analyses of germline and somatic mutations, genome-wide searching for gene-environment interaction, and comparative genomics between US and China. The ultimate goal is to dis- cover genetic markers, both germline and somatic mutations, for early detection and treatment of esophageal adenocarcinoma.